Combined exercise hinders the progression of pulmonary and right heart harmful remodeling in monocrotaline-induced pulmonary arterial hypertension

• Published in: Journal of applied physiology (1985) Vol. 138; no. 1; pp. 182 - 194
• Main Authors: Leite, Luciano Bernardes, Soares, Leôncio Lopes, Portes, Alexandre Martins Oliveira, da Silva, Bruna Aparecida Fonseca, Dias, Taís Rodrigues, Soares, Thayana Inácia, Assis, Mirian Quintão, Guimarães-Ervilha, Luiz Otávio, Carneiro-Júnior, Miguel Araújo, Forte, Pedro, Machado-Neves, Mariana, Reis, Emily Correna Carlo, Natali, Antônio José
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2025
• Subjects: Acceleration; Alveoli; Amplitudes; Animals; Calcium (intracellular); Calcium ions; Carbonyl compounds; Carbonyls; Cardiomyocytes; Catalase; Disease Progression; Exercise; Extracellular matrix; Fitness training programs; Glutathione; Glutathione transferase; Heart; Heart Ventricles - metabolism; Heart Ventricles - physiopathology; Hypertension; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - physiopathology; Load resistance; Lung - metabolism; Lung - physiopathology; Lungs; Male; Monocrotaline; Myocytes; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nitric oxide; Oxidative stress; Oxidative Stress - physiology; Physical Conditioning, Animal - physiology; Physical exercise; Physical training; Physiology; Pulmonary Arterial Hypertension - chemically induced; Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - physiopathology; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - metabolism; Pulmonary Artery - physiopathology; Pulmonary hypertension; Rats; Rats, Wistar; Running; Structure-function relationships; Ventricular Function, Right - physiology; Ventricular Remodeling - physiology; Vertical loads; combined exercise training; remodeling; isolated myocytes; pulmonary arterial hypertension; oxidative stress
• ISSN: 8750-7587; 1522-1601; 1522-1601
• DOI: 10.1152/japplphysiol.00379.2024

This study reveals that combined exercise improves tolerance to physical effort, prevents increases in pulmonary artery resistance, and conserves the right heart function during the progression of pulmonary arterial hypertension. Our analyses show that combined exercise hinders harmful right ventricular and lung structural remodeling and oxidative stress, which reflects in the maintenance of right ventricular myocytes’ contractile function by preserving the intracellular calcium cycling. An attenuated progression of the disease impacts positively on its prognosis. The aim of this study was to test whether combined physical exercise training of moderate intensity executed during the development of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) hinders the progression of pulmonary and right heart harmful functional and structural remodeling in rats. Wistar rats were injected with MCT (60 mg/kg) and after 24 h were exposed to a combined exercise training program: aerobic exercise (treadmill running—60 min/day; 60% of maximum running speed); and resistance exercise (vertical ladder climbing—15 climbs; 60% of maximum carrying load), on alternate days, 5 days/wk, for ∼3 wk. After euthanasia, the lung and right ventricle (RV) were excised and processed for histological, single myocyte, and biochemical analyses. Combined exercise increased the tolerance to physical effort (time until fatigue and relative maximum load) and prevented increases in pulmonary artery resistance (acceleration time (TA)/ejection time (TE)] and reductions in RV function [tricuspid annular plane systolic excursion (TAPSE)]. Moreover, in myocytes isolated from the RV, combined exercise preserved contraction amplitude, as well as contraction and relaxation velocities, and inhibited reductions in the amplitude and maximum speeds to peak and to decay of the intracellular Ca 2+ transient. Furthermore, combined exercise avoided RV (RV weight, cardiomyocyte, extracellular matrix, collagen, inflammatory infiltrate, and extracellular matrix) and lung (pulmonary alveoli and alveolar septum) harmful structural remodeling. In addition, combined exercise restricted RV [nitric oxide (NO) and carbonyl protein (CP)] and lung [catalase (CAT), glutathione S-transferase (GST), and NO] oxidative stress. In conclusion, the applied combined exercise regime hinders the progression of pulmonary and right heart functional and structural harmful remodeling in rats with MCT-induced PAH. NEW & NOTEWORTHY This study reveals that combined exercise improves tolerance to physical effort, prevents increases in pulmonary artery resistance, and conserves the right heart function during the progression of pulmonary arterial hypertension. Our analyses show that combined exercise hinders harmful right ventricular and lung structural remodeling and oxidative stress, which reflects in the maintenance of right ventricular myocytes’ contractile function by preserving the intracellular calcium cycling. An attenuated progression of the disease impacts positively on its prognosis.